The goal of this project is to identify, isolate, and characterize the thyroid-stimulating factor of trophoblastic origin that is responsible for thyroid hyperfunction in patients with trophoblastic tumors. It has been suggested by others that hCG has intrinsic thyrotropic activity and is the thyroid stimulator of molar pregnancy. This project's data support the hypothesis that molar hCG is different from molar TSH and that native hCG is not the thyroid stimulator associated with molar pregnancy. Recent studies have suggested that certain modified forms of hCG have a higher affinity for binding to TSH receptors in thyroid than normal hCG itself. Furthermore, desialylated forms of hCG are reported to be secreted in significant amounts in the urine of patients with choriocarcinoma. Present studies are, therefore, directed at the selective modification of hCG subunits, the recombination of modified subunits, and an assessment of the thyrotropic and gonadotropic activities of such molecules. Studies have indicated that removal of sialic acid residues from either alpha or beta subunits of hCG enhance its binding affinity to receptors in thyroid. In particular, the removal of beta-sialic acid results in greater enhancement of binding than the removal of alpha-sialic acid. In the receptor assay for gonadotropic activity, modification of sialic acid residues on either subunit also results in enhancement of the activity. However, hCG, lacking in sialic acid on the beta subunit, shows substantial loss in in vitro bioassay for gonadotropic activity. Studies are also in progress to characterize the variants of hCG and its subunits that are excreted in normal pregnancy urine and in the urine of patients with trophoblastic tumors in an attempt to identify those that are unique to molar pregnancy. (1)